Our long-term research goal is to develop a surface modification strategy for synthetic-based cell-laden hydrogel scaffolds, which when placed in vivo, facilitates host tissue remodeling at the scaffold-host interface and promotes functional integration of the engineered tissue into the host tissue. Our motivation stems from the fact that when most non-biological materials are implanted into higher organisms, they elicit a foreign body reaction (FBR) resulting in the formation of a thick avascular fibrous capsule. From a tissue engineering perspective, the FBR has received little attention. Our global hypothesis is that the FBR to tissue engineering scaffolds will have a negative impact on cell function and tissue integration - ultimately limiting the utility of synthetic scaffolds in vivo. Specifically, this research tests two hypotheses: i) activation of host inflammatory cells (i.e., macrophages) negatively impacts the function of cells which are encapsulated in PEG-based hydrogels and ii) a thin coating applied to PEG-based hydrogels containing biological signals will inhibit macrophage activation permitting the encapsulated cells to function normally. To test this hypothesis, this research aims to: * evaluate and identify key factors involved in the in vivo host response to poly(ethylene glycol) (PEG)-based hydrogels, which are currently being explored in craniofacial regenerative medicine, by assessing the timing of macrophage recruitment, macrophage activation, and fusion into foreign body giant cells; * develop an in vitro model system that mimics the in vivo environment with respect to macrophage attachment, activation and fusion at the surface of cell-laden PEG-based hydrogels. This model will enable us to study macrophage response when cells are encapsulated in the hydrogel and to study the effect macrophages have on function of the cells encapsulated in the PEG-based hydrogels;and * utilize this model system to develop new strategies aimed at minimizing the FBR. At the completion of these studies, we expect to have demonstrated that macrophage activation and fusion negatively impact encapsulated cells, but that a surface modification strategy can be employed to mitigate this negative effect permitting normal function of the encapsulated cells. In future work, this model system will enable us to study more relevant tissue engineering strategies (e.g., involving stem cells) and to study a wide range of biological signaling molecules, which are currently being explored by Dr. Kyriakides and which have potential for inhibiting macrophage activation. This research will lay the groundwork for designing new tissue engineering strategies that modulate the host response, promote functional tissue development, and enhance integration. This award will position the PI and her collaborator to seek competitively a NIH R01 grant. Public Health Relevance: The clinical success of tissue engineering has been limited, in part, due to a lack of understanding of the host cell response to the material. This research aims to address this deficit by elucidating the host response to hydrogel scaffolds and to develop new methods to modulate this response to promote functional tissue integration.